Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

• Published in: JAMA network open 2020-11, Vol.3 (11), p.e2025839
• Main Authors: Phillips, Nicholas S, Kesler, Shelli R, Scoggins, Matthew A, Glass, John O, Cheung, Yin Ting, Liu, Wei, Banerjee, Pia, Ogg, Robert J, Srivastava, Deokumar, Pui, Ching-Hon, Robison, Leslie L, Reddick, Wilburn E, Hudson, Melissa M, Krull, Kevin R
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adolescent; Adult; Age; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer Survivors; Case-Control Studies; Cerebellum - diagnostic imaging; Cerebellum - pathology; Cerebellum - physiopathology; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Chemotherapy; Chemotherapy-Related Cognitive Impairment - diagnostic imaging; Chemotherapy-Related Cognitive Impairment - physiopathology; Child; Childhood; Community; Dexamethasone - administration & dosage; Executive Function - physiology; Female; Functional Neuroimaging; Glucocorticoids - administration & dosage; Humans; Leukemia; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Methotrexate - administration & dosage; Neural Pathways - diagnostic imaging; Neural Pathways - physiopathology; Neuropsychological Tests; Oncology; Online Only; Organ Size; Original Investigation; Parietal Lobe - diagnostic imaging; Parietal Lobe - pathology; Parietal Lobe - physiopathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Prefrontal Cortex - diagnostic imaging; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Sex Factors; Steroids; Thalamus - diagnostic imaging; Thalamus - pathology; Thalamus - physiopathology; Young Adult
• ISSN: 2574-3805; 2574-3805
• DOI: 10.1001/jamanetworkopen.2020.25839

Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. ALL treatment using chemotherapy-only protocols. This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of b